WO2002049607A2 - Systeme d'administration orale de medicament aromatise - Google Patents
Systeme d'administration orale de medicament aromatiseInfo
- Publication number
- WO2002049607A2 WO2002049607A2 PCT/IB2001/002263 IB0102263W WO0249607A2 WO 2002049607 A2 WO2002049607 A2 WO 2002049607A2 IB 0102263 W IB0102263 W IB 0102263W WO 0249607 A2 WO0249607 A2 WO 0249607A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug delivery
- delivery system
- oral drug
- phase
- flavour
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
Definitions
- the present invention relates to the field of flavoured pharmaceutical compositions. It concerns more particularly a flavoured oral drug delivery system susceptible of masking the unpleasant taste of an active substance to be delivered during a delayed, sustained, or immediate release, and a process for the preparation of such a system.
- the oral drug delivery products represent an important market of the pharmaceutical industry, as they are the most convenient dosage form to administer, the most cost effective to manufacture, and the most preferred by patients.
- This oral solid drug dosage form comprises oral controlled (delayed and/or sustained) release products and oral fast dissolving products.
- Each of these dosage forms provides ease of delivery and is typically cost-effective to manufacture since standard tabletting processes and coating technologies are employed.
- Oral liquid dosage forms such as syrup and dry syrup from solutions, suspensions or emulsions with possible controlled release, are also very popular. They are cheap to manufacture and they are easy to swallow by patients.
- the controlled (delayed and/or sustained) release dosage forms are by far the most commonly used for several reasons : they offer once-daily or twice-daily dosing, reduced frequency of side effects, and are cost-effective to manufacture. Delayed release formulations are similar to the sustained release dosage forms in that they "control" the rate and timing of drug release. However, they do not typically provide constant drug delivery for 12 or 24 hours but they delay release of the drug until the dosage form reaches a certain point in the gastrointestinal track. Fast-dissolving solid dosage forms and liquid dosage forms are ideal for patients who are unable to swallow, have difficulties swallowing, or refuse to swallow.
- the problem of providing a palatable form of an oral drug delivery system intended to deliver an unpleasant tasting drug has often been solved by means of a coating for the active ingredient, preventing its early dissolution in the mouth.
- Materials such as polymers or co-polymers insoluble in water (ethyl cellulose or shellac for instance), or soluble at only certain controlled pH values, are generally used as main constituents of taste-masking coating compositions.
- the thus obtained coated products may be dosed in varied forms.
- JP 200053563 describes bitterness masked microgranules with fast release characteristics.
- the granules comprise cores containing a pharmacologically active substance with bitter taste ; a film coating layer made of water-soluble polymers, and a bitterness masking coating layer containing ethyl cellulose and water-soluble plasticiser.
- This kind of product is intended to be swallowed and is supposed to mask the bitterness of the active material which will be released once swallowed.
- This solution to the problem of taste-masking has several drawbacks, notably that it can happen that a part of the active material is released in the mouth before being swallowed, thus creating an unpleasant bitterness in the mouth or a burning sensation in the throat.
- dosage forms masking the bitterness of non palatable drugs have been described in the prior art, such as systems in the form of chewable tablets for instance, wherein the unpleasant tasting active substance is again coated so as to be protected, and the dosage form, such as a chewable formulation, is further flavoured.
- EP 345628 Bl discloses a solid pharmaceutical dosage in a tablet triturate form, which dissolves quickly and masks the taste of the active ingredient. More particularly, the active ingredient is encapsulated in a triglyceride vehicle and the thus obtained particles are uniformly distributed in a porous cementatory network substantially constituted by a carbohydrate.
- the dosage form includes acceptable excipients, such as flavouring, sweetening and colouring agents.
- the dosage form is flavoured in such a way that the chewable tablet tastes pleasant.
- the active ingredient itself is not flavoured, but is only protected by a coating layer. Consequently, here again, some active ingredient may always be released in the mouth and thus provoke a bitter taste or burning sensation in the throat. In fact, the film resistance to chewing is low, so that the unpleasant sensations are never fully covered.
- One object of the present invention is therefore an oral drug delivery system comprising an unpleasant tasting active substance incorporated in a solid or liquid phase, here-after referred as the "active phase”, characterised in that a neutral flavour is dispersed or solubilized in said phase.
- active phase characterised in that a neutral flavour is dispersed or solubilized in said phase.
- neutral flavour it is understood here an ingredient or a composition susceptible of imparting, modifying or improving the organoleptic properties and/or mouthfeel of a material, without necessarily imparting a specific taste to it.
- the neutral flavour according to the present invention is a flavouring ingredient or a flavouring composition used at a concentration sufficiently low to prevent the perception by the user of any flavour tonality.
- the system of the invention is not based on the traditional addition of flavour to a tablet core as disclosed in the prior art, but on the addition of a taste masking flavour, defined as having a neutral taste, directly into the phase comprising the active ingredient, in such a way that the final product, namely solid, soft or liquid particles comprising said active ingredient, also include a taste-masking flavour.
- the addition of the neutral flavour advantageously decreases the concentration of the active ingredient at the particle surface as a consequence of a dilution effect.
- a targeted flavour release system is designed to release the flavour only when and where necessary.
- the delivery system of the invention therefore provides an efficient solution, applicable to any kind of dosage form and which assures the masking of bitterness or of any other unpleasant sensation of an active material during its release.
- the active phase constituted by the active ingredient and the neutral flavour in the form of discrete solid, soft or liquid particles, may then be uniformly dispersed in a support phase which contains excipients required for the release, preservatives, colouring ingredients of the dosage form, and a second flavour giving the overall flavour profile to the dosage form.
- the oral drug delivery system according to the present invention comprises an unpleasant tasting active substance incorporated in an active phase, wherein a neutral flavour is dispersed.
- the incorporation in a solid or liquid phase of the active material together with the neutral flavour may be carried out by way of encapsulation, adsorption, melting or emulsification.
- Encapsulation is meant to refer to a variety of conventional techniques which may be used to provide solid sphere shaped particles, in particular spheroid like, which uniformly incorporate the active material with the neutral flavour dispersed in a matrix.
- Discrete particles are therefore produced by first dispersing or dissolving the active ingredient and the neutral flavour in a polymeric vehicle (matrix) which additionally may contain additives to modify the rate and extent of drug release from the particles. This suspension or solution is then encapsulated.
- the active phase thus obtained, in the form of spheroid particles, provides a uniform distribution of the active material and of the neutral flavour. Both are retained throughout the matrix in a homogeneous manner, such that, in case of release, the active material, which texture or mouthfeel has been modified by the presence of the neutral flavour, is no longer unpleasant (bitterness, burning sensation) for the patient.
- Adsorption is meant to refer to a variety of conventional techniques which may be used to provide stable solid adsorbate complexes which uniformly incorporate the active material with the neutral flavour.
- Melting is meant to refer to a variety of conventional techniques which may be used to provide stable solid particles where the active material is finely dispersed or solubilized in a melting carrier. After cooling and milling, uniform calibrated particles incorporating the active material with the neutral flavour are obtained.
- the particle size is usually comprised between 10 nm and 2 mm.
- the neutral flavour which is incorporated in the active phase, together with the active substance, is capable of improving, modifying or enhancing the organoleptic properties of the latter, while having a tonality which is not readily identifiable.
- This ingredient is preferably selected from the group consisting of 2-hydroxy-3-methyl-2- cyclopenten-1-one and derivatives, n-octanal, n-decanal, citral, Furaneol ® (4-hydroxy-
- the proportions in which the neutral flavour can be added to the matrix are sufficiently low to prevent the identification of the flavour tonality.
- the values thus depend on the detection threshold of the flavouring ingredient or composition.
- Suitable matrix compositions are based on the use of common polymers selected from the group consisting of water insoluble hygroscopic excipients such as micro-crystalline cellulose, powdered cellulose, sodium starch glycolate, cross-linked and non cross-linked polyvinylpyrrolidone, cellulose esters such as cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxylpropyl methylcellulose, ethylcellulose, carboxymethyl ethylcellulose, gelatin, polymethacrylic acid co-polymers such as Eudragit " L30D, Eudragit ® NE 30D, Eudragit ® RL 30D (origin : Rohm GmbH Degussa-Huls civil, Kirschenalle, Darmstadt, Germany), comprising or not a plasiticizer chosen from the group consisting of glyceryl triacetate, triethyl citrate, acety
- Suitable adsorbing agents can be selected from the group consisting of magnesium trisilicate, fumed silica and mixtures thereof.
- Suitable carriers for melting can be selected from the group consisting of maltodextrins, saccharose, xylitol, sorbitol, other polyols and mixtures thereof.
- Suitable categories of active substances that may be incorporated in the active phase vary widely and generally represent any stable drug composition.
- Illustrative categories and specific examples include antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrohloride ; histamine H) -receptor antagonists, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate and phenyltoloxamine citrate ; histamine H 2 -receptor antagonists, such as ranitidine, famotidine, cimetidine, nizatidine and roxatidine ; decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, hydrochloride ephedrine ; various alkaloids, such as codeine phosphat
- Additional useful active medicaments include coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, antimanics, stimulants, gastro-intestinal sedatives and bandages, antidiarrheal and anticonstipation preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors and migraine treatments, antibiotics, tranquilizers, antiphychotics, antitumor drugs, anticoagulants, and antithrombotic drugs, hypnotics, sedatives, antiemetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypoglycaemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, antihistaminic or anticholinergic or opiate derivatives (such as
- the active material is constituted by a slightly water soluble bitter active ingredient selected from the group consisting of ibuprofen, ketoprofen, fenoprofen calcium and acetaminophen (origin : Albermarle Corp.).
- the active phase according to the present invention usually contains from 1 to 90 parts by weight of active substance, preferably from 30 to 90 parts by weight, and from 0.1 to 20 parts by weight of neutral flavour.
- the active phase may also comprise additional ingredients such as sweeteners, colouring agents, anticaking and lubricant agents.
- the active phase consisting of particles encapsulating or incorporating the active substance and the neutral flavour is advantageously dispersed in a support phase comprising at least one flavouring ingredient.
- a support phase comprising at least one flavouring ingredient.
- the latter is intended to give the overall flavour profile to the dosage form.
- suitable flavours include synthetic flavour oils and/or oils derived from plants, leaves, roots, flowers, fruits, as well as corresponding extracts and combinations thereof.
- flavour oils include spearmint oil, peppermint oil, cinnamon oil, or oil of wintergreen.
- artificial natural or synthetic fruit flavours such as citrus oils including lemon, orange, lime, tangerine and grapefruit, and fruit essences including apple, strawberry, cherry, pineapple.
- suitable materials can easily be selected by the expert flavorist and can be found in art textbooks such as, for example, Fenarolli's.
- flavouring ingredient is added to the support phase vary in a broad range of values. These values depend on the nature of the support phase and on the organoleptic effect desired, as well as on the nature of the possible co- flavouring ingredients. For instance, concentrations form 0.01 to 10% by weight of the flavouring compound with respect to the weight of the support phase in which it is incorporated can be used.
- the support phase may comprise excipients required for the release, the preservation, and/or the colour properties of the dosage form.
- the support phase may consist of a free flowing or compressed solid, or a liquid.
- the support phase is fast-dissolving in the buccal cavity and is substantially constituted of lactose (Flowlac ® ; origin : Meggle GmbH, Wasserburg, Germany) and hydrate dextrates.
- the system of the invention can be used for example, in the form of a dry or liquid (emulsion or suspension) syrup, a sachet, a chewable, an orodispersible, a dispersible effervescent or a dispersible tablet or a liquid flavour.
- the discrete particles can constitute 0.1 to 70% by weight of the dosage form.
- the final product is in the form of a chewable tablet and the support phase is a compressed solid, which may include other adjuvants normally used in the preparation of chewable tablets, including diluants, binders, disintegrants, lubricant, colours and sweeteners.
- Another object of the present invention is a process for the preparation of an oral drug delivery system, characterised in that it comprises the step of incorporating an unpleasant tasting active substance in an active solid or liquid phase (referred to as the "active phase"), including a dispersed or solubilized neutral flavour.
- the active substance and the neutral flavour are incorporated in said active phase by way of an encapsulation technique such as those cited above.
- the active material and the neutral flavour are encapsulated by way of extrusion.
- the basic process for preparing the solid particles comprises the steps of combining and blending the active substance and the neutral flavour with an extrudable matrix material, an emulsifier and optionally a plasticiser under controlled temperature and stirring conditions useful to produce a uniform melt thereof ; extruding the molten mass through a die ; chopping and cutting, grinding or pulverising the material obtained as it exits the die or after having cooled the molten mass ; and optionally drying.
- Extrusion processes are described in literature for instance in WO 00/25606, the content of which is hereby included by reference.
- the encapsulation of the active material and neutral flavour is effected by wet granulation. More particularly, the process comprises the steps of wet granulating both ingredients with a microcrystaline cellulose composition and then spheronizing the granulation into spheres having a smooth uniform surface, as described in WO 99/17748 hereby included by reference. The discrete particles obtained by encapsulation may then be distributed in a substantially uniform way throughout a support phase, as defined above.
- a mixture was prepared by admixing ibuprofen (Albemarle Corp.), Avicel ® (Sphere Grade, FMC Corporation), and dicalcium phosphate in proportions given in
- Example 1 of WO 99/17748 here-included by reference There were added 5% by weight of a neutral vanilla flavour in a spray-dried form, prepared by admixing the following ingredients :
- the chewable tablet was prepared as described in Example 2 of WO 99/17748, using the solid spheres prepared according to a).
- a mixture was prepared by admixing 25 g of quinine hydrochloride (origin : Chemische Fabrik Schweizerh, Basel, Switzerland) in a 250 ml aqueous solution of starch at 1.8% w/w. The solution had a total load of quinine hydrochloride of 10.80%. This solution was then sprayed on sugar spheres (suglets ; origin : NP Pharm SA, Bazainville, France) in a Strea 1 Niro aeromatic spray dryer (origin :
- a spraying solution comprising the neutral flavour was prepared as follows : 200 ml of water were placed in a beaker, to which 3.08 g of sodium lauryl sulfate (origin : Henkel KGaA, D ⁇ sseldorf, Germany) and 6.60 g of dibutyl sebacate (origin : Fluka) were further added. The mixture was then slowly stirred in 44 g of Eudragit R EPO (origin : Rohm GmbH Degussa-H ⁇ ls civil, Kirschenalle, Darmstadt, Germany) with a propeller stirrer to avoid lump formation. After 2 hours of continued stirring to ensure total solubilisation of the polymer, 1.17 g of a spray-dried caramel neutral flavour were added to the solution.
- Said flavour comprised the following ingredients : Ingredients Parts by weight
- the active particles prepared under a) were partly (55 g) placed in a pan coating and blend with 125 g of uncoated sugar spheres.
- the spraying solution comprising the neutral flavour was sprayed on separate blends of sugar spheres thus forming a flavoured taste-masked active ingredient.
- Orodispersible tablets were prepared from respectively, 48 mg of non taste-masked (NTM) quinine sugar spheres a), 64 mg of flavoured taste-masked (FTM) quinine sugar spheres b), and 52 mg of unflavoured taste-masked (UTM) quinine sugar spheres c), using the following base per tablet :
- NTM, FTM and UTM were chosen in order to ensure that the tablets a), b), and c), contained similar quinine load.
- the orodispersible tablets a), b) and c) were evaluated on a blind test by a panel of 6 people. The 6 persons established that the taste-masking was clearly improved from NTM to FTM products.
- Example 2 was repeated, flavouring the taste-masked quinine spheres of step b) with 1.40 g of a liquid flavour comprising the following ingredients :
- a solution was prepared by admixing 37 g of quinine hydrochloride (origin : Chemische Fabrik Schweizerh, Basel, Switzerland) with 100 g of propylene glycol and 175 ml of water, 1.90 g of a neutral flavour were added to this solution.
- Said flavour comprised the following ingredients :
- Adsorbate granules were then prepared, following the procedure described in Example 1 of WO 95/03785, the contents of which is hereby included by reference.
- sample a the first one containing a neutral flavour incorporated in its active phase
- sample b the other one, having an active phase free of neutral flavour
- two other delivery systems, c), and d) were prepared (using the same ingredients and same proportions for the support phase) : c) : wherein the active phase comprised the hydrochloride quinine as such (i.e. not adsorbed on a carrier), and the support phase was flavoured with a mixture of strawberry flavour and neutral flavour. d) : wherein the active phase comprised the hydrochloride quinine as such (i.e. not adsorbed on a carrier), and the support phase was flavoured with strawberry flavour.
- the four delivery systems there-prepared, a), b), c), and d) were evaluated on a blind test by a panel of 15 people who were asked to evaluate on the one hand, the bitterness of the samples and on the other, the flavour intensity of the samples, on a scale ranging from 1 (lowest bitterness/flavour intensity) to 10 (highest bitterness/flavour intensity).
- the bar diagrams reported on page 1/1 (Fig. 1 and Fig. 2) give the results of these evaluations.
- FIG. 2 The diagram reporting the flavour intensity (Fig. 2) shows that the neutral flavour does not significantly influence the flavour intensity, whatever the phase where it is incorporated, which confirms its "neutral” nature, i.e. the fact that it cannot be perceived as such in the final product.
- the diagram reporting the bitterness evaluation clearly demonstrates the bitterness masking effect of the neutral flavour present in the active phase. More particularly, it can be stated firstly that the bitterness is perceived almost equally intensively when there is no neutral flavour ⁇ d)) or when the neutral flavour is in the support phase ⁇ c)). In other words, the neutral flavour has no effect on bitterness evaluation when added to the support phase. Furthermore, the bitterness, which is already perceived less intensively when the active phase is constituted by quinine adsorbed on the carrier ⁇ b)), is perceived even weaker to the panellists when the active phase comprises the neutral flavour adsorbed with quinine on the porous carrier ⁇ a)). The positive effect of the neutral flavour incorporated directly in the active phase is thus demonstrated.
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Abstract
La présente invention concerne un système d'administration orale de médicament aromatisé permettant de masquer le goût déplaisant d'un principe actif devant être administré en vue d'une libération retardée, prolongée ou immédiate. L'invention concerne également un procédé permettant de préparer un tel système.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IBPCT/IB00/01934 | 2000-12-20 | ||
IB0001934 | 2000-12-20 |
Publications (2)
Publication Number | Publication Date |
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WO2002049607A2 true WO2002049607A2 (fr) | 2002-06-27 |
WO2002049607A3 WO2002049607A3 (fr) | 2003-03-20 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IB2001/002263 WO2002049607A2 (fr) | 2000-12-20 | 2001-11-27 | Systeme d'administration orale de medicament aromatise |
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005053421A2 (fr) * | 2003-12-01 | 2005-06-16 | Hill's Pet Nutrition, Inc. | Composition a l'appetibilite renforcee, et procede pour la consommation par les animaux |
WO2007041367A3 (fr) * | 2005-09-30 | 2007-11-29 | Mcneil Ppc Inc | Préparation orale contenant un agent induisant la salivation |
CN100386086C (zh) * | 2006-03-09 | 2008-05-07 | 山东山大康诺制药有限公司 | 一种复方甘草酸及其盐的分散片剂及其制备方法 |
US7867540B2 (en) | 2005-07-19 | 2011-01-11 | Mars, Inc. | Aroma composition and method |
US20120010218A1 (en) * | 2002-01-15 | 2012-01-12 | Domenico Fanara | Formulations |
JP2014090676A (ja) * | 2012-10-31 | 2014-05-19 | Kirin Beverage Corp | トリテルペンまたはその配糖体の呈味改善剤 |
US20160113867A1 (en) * | 2013-06-05 | 2016-04-28 | Pharnext | Stable oral solutions for combined api |
WO2017025342A1 (fr) * | 2015-08-10 | 2017-02-16 | Rhodia Operations | Procede d'encapsulation |
US10322101B2 (en) | 2007-11-30 | 2019-06-18 | Pharnext | Therapeutic approaches for treating CMT and related disorders |
US10383870B2 (en) | 2016-06-10 | 2019-08-20 | Pharnext | Early treatment of CMT disease |
US10583135B2 (en) | 2009-06-02 | 2020-03-10 | Pharnext | Compositions for treating CMT and related disorders |
US10905686B2 (en) | 2009-06-02 | 2021-02-02 | Pharnext | Compositions for treating CMT and related disorders |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20120010218A1 (en) * | 2002-01-15 | 2012-01-12 | Domenico Fanara | Formulations |
WO2005053421A3 (fr) * | 2003-12-01 | 2006-10-26 | Hills Pet Nutrition Inc | Composition a l'appetibilite renforcee, et procede pour la consommation par les animaux |
WO2005053421A2 (fr) * | 2003-12-01 | 2005-06-16 | Hill's Pet Nutrition, Inc. | Composition a l'appetibilite renforcee, et procede pour la consommation par les animaux |
US7867540B2 (en) | 2005-07-19 | 2011-01-11 | Mars, Inc. | Aroma composition and method |
WO2007041367A3 (fr) * | 2005-09-30 | 2007-11-29 | Mcneil Ppc Inc | Préparation orale contenant un agent induisant la salivation |
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CN100386086C (zh) * | 2006-03-09 | 2008-05-07 | 山东山大康诺制药有限公司 | 一种复方甘草酸及其盐的分散片剂及其制备方法 |
US10322101B2 (en) | 2007-11-30 | 2019-06-18 | Pharnext | Therapeutic approaches for treating CMT and related disorders |
US10463640B2 (en) | 2007-11-30 | 2019-11-05 | Pharnext | Therapeutic approaches for treating CMT and related disorders |
US10441558B2 (en) | 2007-11-30 | 2019-10-15 | Pharnext | Therapeutic approaches for treating CMT and related disorders |
US10583135B2 (en) | 2009-06-02 | 2020-03-10 | Pharnext | Compositions for treating CMT and related disorders |
US11672796B2 (en) | 2009-06-02 | 2023-06-13 | Pharnext | Compositions for treating CMT and related disorders |
US11576908B2 (en) | 2009-06-02 | 2023-02-14 | Pharnext | Compositions for treating CMT and related disorders |
US10905686B2 (en) | 2009-06-02 | 2021-02-02 | Pharnext | Compositions for treating CMT and related disorders |
JP2014090676A (ja) * | 2012-10-31 | 2014-05-19 | Kirin Beverage Corp | トリテルペンまたはその配糖体の呈味改善剤 |
US20160113867A1 (en) * | 2013-06-05 | 2016-04-28 | Pharnext | Stable oral solutions for combined api |
US10849851B2 (en) | 2013-06-05 | 2020-12-01 | Pharnext | Stable oral solutions for combined API |
US10300015B2 (en) * | 2013-06-05 | 2019-05-28 | Pharnext | Stable oral solutions for combined API |
WO2017025342A1 (fr) * | 2015-08-10 | 2017-02-16 | Rhodia Operations | Procede d'encapsulation |
CN108135859A (zh) * | 2015-08-10 | 2018-06-08 | 罗地亚经营管理公司 | 封装方法 |
FR3039990A1 (fr) * | 2015-08-10 | 2017-02-17 | Rhodia Operations | Procede d'encapsulation |
US11071318B2 (en) | 2015-08-10 | 2021-07-27 | Rhodia Operations | Encapsulation process |
JP2018532817A (ja) * | 2015-08-10 | 2018-11-08 | ローディア オペレーションズ | 封入方法 |
US10383870B2 (en) | 2016-06-10 | 2019-08-20 | Pharnext | Early treatment of CMT disease |
US10940147B2 (en) | 2016-06-10 | 2021-03-09 | Pharnext | Early treatment of CMT disease |
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WO2002049607A3 (fr) | 2003-03-20 |
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